PROJECT SUMMARY/ABSTRACT Aggression and violence are common symptoms of many psychiatric disorders, but the underlying mechanisms that lead to their expression remain largely unknown. The amygdala is a key region involved in the regulation of emotion and has been implicated as a primary locus of psychopathology. The medial amygdala (MeA) is a major subdivision of the amygdala and is an important modulator of aggression and violence. Previous studies have shown that high-frequency stimulation of neurons at the MeA can enhance aggression during future social encounters, producing a phenomenon called aggression priming. The precise mechanism by which the medial amygdala mediates aggression and its role in psychiatric illness, however, requires further elucidation. The goal of this PRAT fellowship proposal is to define the role of the MeA in aggression. My preliminary results show that glutamatergic neurons within the MeA respond to stimulation in a frequency-dependent manner and that the MeA can regulate expressions of aggression and violence during a social interaction test. My central hypothesis is that potentiation of glutamatergic synapses at the MeA can prime aggression, leading to an increase in aggression and violence during social interaction. Firstly, I plan to determine whether high-frequency photostimulation (HFPS) using optogenetics can induce aggression priming during a social interaction test. I will test whether HFPS induces synaptic potentiation at the MeA using in vivo electrophysiology and whether synaptic potentiation is responsible for aggressive behavior by depotentiating synapses after HFPS using low-frequency photostimulation, a known protocol for inducing depression of synaptic activity. Secondly I will determine the role of serotonin in MeA regulated aggression by stimulating dorsal raphe projections, a primary locus of serotonergic neurons, at the MeA using optogenetics. Finally I will confirm the role of serotonin in MeA regulated aggression using genetic modifications to the serotonin releasing machinery in vivo and specialized sensors designed to detect serotonin binding at the MeA. The successful completion of this proposal will have a positive translational impact because preventative therapeutic strategies targeting the MeA can potentially be developed to curb excessive aggression and violence associated with psychiatric disorders based on the findings of the proposed research.